Clarke-Eschweiler alkylation

The previous sections have dealt with stable C=N-I- functionality in aromatic rings as simple salts. Another class of iminium salt reactions can be found where the iminium salt is only an intermediate. The purpose of this section is to point out these reactions even though they do not show any striking differences in their reactivity from stable iminium salts. Such intermediates arise from a-chloroamines (133-135), isomerization of oxazolidines (136), reduction of a-aminoketones by the Clemmensen method (137-139), reductive alkylation by the Leuckart-Wallach (140-141) or Clarke-Eschweiler reaction (142), mercuric acetate oxidation of amines (46,93), and in reactions such as ketene with enamines (143). 

The reductive alkylation reaction under Clarke-Eschweiler conditions has been shown to proceed through an iminium intermediate (142). 

Amine synthesis from reductive amination of a ketone and an amine in the presence of excess formic acid, which serves as the reducing reagent by delivering a hydride. When the ketone is replaced by formaldehyde, it becomes Eschweiler-Clarke reductive alkylation of amines. 

N-Methylation of secondary amines is usually accomplished either with CH20/HC02H (Leuckart/Clarke-Eschweiler reaction) or with CH20 followed by NaBH4 reduction. Methyl iodide treatment of secondary or tertiary bisben-zylisoquinoline alkaloids leads ultimately to the bis quaternary salts, and, in the presence of base, phenolic alkaloids are also O-alkylated. For example, lin-doldhamine (165) on treatment with ethyl bromide in 0.5 N ethanolic KOH gave the N,N,0,0,0-pentaethy 1 derivative (108, Section II,C,56) daurisoline was similarly permethylated with Mel and base (68, Section II,C,19). 

Brewer, A. R. E. Eschweiler-Clarke reductive alkylation of amine. In Name Reactions for Functional Group Transformations-, Li, J. J., Corey, E. J., eds. John Wiley Sons Hoboken, NJ, 2007, pp 86-111. (Review). 

The related Clarke-Eschweiler reaction in whidi the reductive alkylation of an amine is carried out with formaldehyde and formic acid was used to prepare 3-dimethylamino-l-phenyl-1-(2-pyridyl)ptopane (IX-2S8) from 3-phenyl-3-(2-pyridyl)propylamine (IX-257). ... 

A useful application is the Clark-Eschweiler reductive alkylation of amines. Heating a primary or secondary amine with formaldehyde and formic acid results in complete methylation to the tertiary amine. The hydride acceptor is the iminium ion resulting from condensation of the amine with formaldehyde. 

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